LncRNA FRMD6-AS1 promotes hepatocellular carcinoma cell migration and stemness by regulating SENP1/HIF-1α axis

Background: Long non-cording RNAs (lncRNAs) drive the malignant progression of hepatocellular carcinoma (HCC), a cancer with high mortality rates but the function of FERM Domain Containing 6 antisense RNA 1 (FRMD6-AS1) in HCC has not been fully addressed. Hypoxia-inducible factors (HIFs) are transcription factors relevant to HCC under hypoxia and are regulated by SUMO-specific protease 1 (SENP1) through its deSUMOylation of HIF-1α. The current study investigated the role of FRMD6-AS1 in the regulation of SENP1-mediated deSUMOylation of HIF-1α.

Methods: HUH7 and MHCC97H cells were treated with CoCl₂ to mimic hypoxia in vitro and lentiviral vector-mediated FRMD6-AS1 overexpressing HCC cells were established. Wound-healing, Transwell, sphere formation assay, Western blotting analysis and animal experiments were performed. Expression of FRMD6-AS1, SENP1 mRNA and HIF-1α mRNA was assessed by RT-qPCR and of HIF-1α and SENP1 protein by Western blot. DeSUMOylation of HIF-1α was detected by immunoprecipitation. RNA immunoprecipitation with SENP1 antibody or IgG was performed to assess endogenous interactions between SENP1 and FRMD6-AS1.

Results: FRMD6-AS1 was upregulated in HCC tissues and cells and its upregulation indicated poor prognosis for HCC patients. FRMD6-AS1 promoted HCC cells migration and stemness in vitro and also promoted tumor growth in an in vivo mouse xenograft model. Mechanistic studies showed that FRMD6-AS1 regulated the level of HIF-1α protein but not the mRNA and this effect was achieved by binding to SENP1 protein and enhancing its protease activity. Rescue experiments demonstrated the oncogenic role of the FRMD6-AS1/SENP1/ HIF-1α axis in HCC cells.

Conclusions: High FRMD6-AS1 expression was associated with poor prognosis of HCC patients. FRMD6-AS1 may have an oncogenic role in HCC via regulation of the SENP1/HIF-1α axis and may be a prognostic biomarker for HCC. Blockade of FRMD6-AS1 may offer a novel therapeutic approach to restrict HCC progression.